The menopause is an impairment of ovarian function accompanied by high levels of follicle-stimulating hormone (FSH) and lower levels of estradiol (E2). The time up to the last menstruation is also referred to as “perimenopause”. During this period, most women notice cycle irregularities which last for 1 to 5 years. In most western countries, about 80% of peri- and postmenopausal women suffer from hot flushes, in about 30% of them the hot flushes are so severe and frequent that the quality of life is noticeably impaired thereby. The exact physiological cause of hot flushes is unknown (Ginsburg, Obstetrics and Gynecology Clinics of North America 1994; 21 (2): 381-390). Hot flushes follow a release of gonadotropin-releasing hormone (GnRH) from the hypothalamus and are not linked to changes in the level of estradiol and estrone. They are accompanied by the release of luteinizing hormone (LH), corticotrophin, growth hormone and β-lipotrophin from the pituitary and of dehydroepiandrosterone and androstenedion from the adrenal. FSH levels may vary between normal and high (>20 IU/l).
Hormone replacement therapy (HRT) replaces the two female sex steroids estrogen and progesterone. HRT was employed for many years for the treatment of menopausal symptoms and for preventing cardiovascular disorders and osteoporosis in the peri- and postmenopause. It was regarded as effective and safe. However, this is no longer true since large randomized controlled studies were carried out and showed the contrary (Beral et al., Lancet 2002; 360: 942-944, Collaborative Group, Lancet 1997; 359: 1047-1059). HRT has no positive effect on the incidence and progression of coronary heart disease. There is in fact evidence that it increases the risk of cardiovascular disorders in peri- and post menopausal women. In a randomized, placebo-controlled double-blind study of primary prevention with estrogen plus progestin, carried out by the Women's Health Initiative (WHI), 100% more thromboses, 41% more strokes and 29% more myocardial infarctions compared with placebo found after HRT (Writing Group for WHI Investigators JAMA 2002; 288: 321-333, Chlebowsky et al. JAMA 2003; 289: 3243-3253). In addition, it has been found in randomized controlled studies that HRT is linked to an increased risk of the occurrence of breast cancer (Million Women Study Collaborators Lancet 2003; 362: 419-427, Schairer et al. JAMA 2000; 283: 485-491, Ross et al. J Natl Cancer Inst 2000; 92: 328-332, Colditz et al. N Engl J Med 1995; 332: 1589-1593, Magnusson et al. Int J Cancer 1999; 81: 339-344).
The estrogen receptor (ER) mediates the activity of estrogens in regulating a number of important physiological processes, including the development and function of the female reproductive system. Whereas stimulation of processes in these tissues has important health advantages, the cancer risk may be increased by stimulation of other tissues such as the breast and the uterus, especially in the peri- and postmenopause. The ER family comprises two subtypes, namely ERα and ERβ. Studies with ER-selective knockout mice have shown that the typical unwanted estrogen effects such as endometrial hyperplasia and breast cancer are mediated by ERα, or as ERβ acts as a negative regulator of ERα and is important for protecting against hyperproliferation and carcinogenesis in tissues in which both receptors are coexpressed (Hewitt et al. Breast Cancer res 2003; 2: 345-352, Frasor et al. Endocrinology 2003; 144: 3159-3166, Lindberg et al. Mol Endocrinol 2003; 17: 203-208).
Based on the results of clinical and experimental studies, increasing numbers of women refuse to use HRT for their menopausal symptoms. In addition, HRT is not indicated for treating women who already have an endocrine-dependent tumor, or show a high cancer risk, especially breast cancer and endometrial cancer. For these reasons, novel active ingredients for treating menopausal symptoms which are free of the potential risks associated with HRT, especially also on long-term use, are very desirable.
There are a number of so-called phytoestrogens which have claims to be effective in relation to reducing hot flushes and sweating episodes. For most of these herbal products, the results of clinical studies, where in fact available, are contradictory or show no efficacy by comparison with placebo. In addition, some constituents of these products may have an estrogenic activity despite their relatively weak binding affinity for ERα (e.g. genistein, coumestrol, equol and zearalenone; Müller et al. Toxicol. Sci. 2004; 80: 14-25) and thus represent the risks similar to HRT. It has in fact been observed that long-term treatment with soya phytoestrogens led to endometrial hyperplasia (Unfer et al., Fertil Steril 2004; 82: 145-148). These observations cast doubt on the long-term safety of phytoestrogens, especially in relation to the endometrium.
There is thus a great need for novel active ingredients or active ingredient combinations for treating menopausal symptoms which do not bind to ERα, i.e. are not procarcinogenic, and do not promote the development of cardiovascular disorders.
Since 1993, a dry extract of roots of Rheum rhaponticum has been on the market in Germany under the name Extrakt Rheum rhaponticum (ERr 731®) (proprietary name Phytoestrol® N) for follicle hormone replacement therapy, for example for treating women with menopausal symptoms, juvenile oligomenorrhea and dysmenorrhea, primary and secondary amenorrhea, and endometritis. The constituents of the specific ERr 731® extract are rhaponticin, deoxyrhaponticin, rhapontigenin and deoxyrhapontigenin (table 1).
TABLE 1Composition of the extract ERr 731 ®HydroxystilbeneChemical nameCAS No.Rhaponticin3,3′,5-Trihydroxy-4′-155-58-8methoxystilbene 3-O-β-D-glucopyranosideDeoxyrhaponticin3′,5-Dihydroxy-4′-30197-14-9methoxystilbene 3-O-β-D-glucopyranosideRhapontigenin3,3′,5-Trihydroxy-4′-500-65-2(trans-Rhapontigenin)methoxystilbeneDeoxyrhapontigenin3′,5-Dihydroxy-4′-methoxystilbene33626-08-3
All of the constituents of ERr 731® belong to the group of hydroxystilbenes. Several studies have shown that the number and position of the free hydroxy and methoxy groups strongly influences the biological activity of the hydroxystilbenes. The pharmacological effect of the hydroxystilbenes is moreover dependent on the presence of a glucose group.
 R1R2R3ResveratrolOHHOHRhaponticinOCH3OHO-GlcDeoxyrhaponticinOCH3HO-GLcRhapontigeninOCH3OHOHDeoxyrhapontigeninOCH3HOHAstringinOHOHO-GlcPiceatannolOHOHOH(astringenin)
There has been only inadequate investigation of whether, and to which metabolites, the constituents of ERr 731® are degraded in the body for example after oral administration. Thus, it is merely known from investigations on the antithrombotic and antiallergic activity of rhaponticin-containing extracts from rhizoma rhei that rhaponticin is degraded by bacteria of the human intestinal tract to rhapontigenin (Park et al, Arch. Pharm. Res. 2002, 25 (4), 528-533). Metabolism of rhaponticin to piceatannol or of deoxyrhaponticin to resveratrol has not been observed to date.
The commercially available product ERr 731® (proprietary name Phytoestrol® N) shows certain disadvantages in relation to dosage form and production. In particular, the absolute active ingredient content in the commercial product is relatively low, so that the dosage form for a dose of, for example, 4 mg of active ingredient is relatively large (400 mg tablet), which is found on occasion to be disadvantageous for oral administration.
The size of the dosage form additionally has disadvantageous effects on the production costs, because a disproportionately large content of formulation ancillary substances is present relative to the amount of active ingredient, in turn unnecessarily increasing the production costs. A size reduction of the solid dosage form is not easily achieved, since when the size of the dosage form is reduced, the limit for the permissible variation in active ingredient content becomes increasingly difficult to comply with. This is true in particular of active ingredients of the present type, which are very prone to become inhomogeneous during production of the solid dosage form, especially of the active ingredient-containing tablet core.
Since active ingredient release in the intestine is desired in some cases for the solid dosage forms employed for the above indication, conventional formulations are provided with a gastro-resistant coating. Coatings of this type usually include a plasticizer, to prevent unwanted formation of cracks, which frequently leads to intolerances such as, for example, allergies, especially on prolonged intake of the medicament. On the other hand, if cracks occur there is the risk of causing stomach ache. Crack resistant but plasticizer-free, gastro-resistant solid formulations would therefore likewise be desirable.
Disadvantages of solid oral dosage forms currently on the market are on occasion also to be seen in the fact that the ingredients are unable to act immediately because the release takes place only with a certain time lag, and thus treatment of acute symptoms such as suddenly occurring migraines or hot flushes is not optimal. In addition, conventional solid dosage forms can be administered only systemically and not locally, this being disadvantageous in the case of locally restricted health impairments such as, for example, the occurrence of vaginal problems with no other menopausal symptoms in addition. Moreover, individual dosage of solid dosage forms, especially gastro-resistant tablets, is possible to only a limited extent because they are not divisible, which likewise may be disadvantageous. Alternative dosage forms, which can be employed as required, of the above active ingredients would therefore be desirable.
Against the provision of dosage forms which are not designed for oral administration, such as, for example, gels for local application, is also the fact that it has to date been assumed that the resveratrol and piceatannol precursors such as rhaponticin and deoxyrhaponticin are pharmacologically inactive per se and show an effect only through metabolism to resveratrol and piceatannol after oral administration.
FR 2 835 185 describes a complex rhubarb extract obtainable from rhizomes of Rheum rhaponticum, which is said to be characterized in that it comprises at least 50% hydroxystilbenes, with at least 50% of these hydroxystilbenes consisting of rhaponticin, deoxyrhaponticin, astrangin and piceatannol. A preferred extract comprises 15-50% by weight rhaponticin, 10-35% by weight deoxyrhaponticin, 5-10% by weight astrangin and 0.1-3% by weight piceatannol. This extract is, as illustrated in the examples, prepared by hydroalcoholic extraction of rhizomes of Rheum rhaponticum. The total content of rhaponticin and deoxyrhaponticin which can be obtained thereby is only 76% by weight. The content of astrangin comprises 11% by weight, the content of piceatannol comprises 3% by weight, and the content of anthracenosides comprises 0.5% by weight. In addition thereto, this extract appears to comprise about 10% by weight further undefined constituents. It is additionally asserted in FR 2 835 185 that the specific extract therein has, as a result of alleged synergistic effects of the various ingredients of the extract, biological properties which are considerably superior to the effect of the individual hydroxystilbenes, especially those effects which the ingredients described therein are said to have individually. The extract described therein is alleged to have antioxidant, antitumor, antiinflammatory and estrogenic properties. However, in fact, FR 2 835 185 does not provide a verifiable technical teaching for the asserted pharmacological usability, to say nothing of the asserted synergistic effect of the complex drug extract described therein. The experimental section describes merely individual formulation examples of capsules, tablets or creams. In particular, experimental data proving the alleged usability for the treatment of disorders connected with free radicals, such as, for example, accelerated aging, cancer, arteriosclerosis, wrinkles, inflammatory phenomena and the like, are completely lacking. The asserted suitability of a combination of the rhubarb extract described therein with a hop extract rich in prenyl flavonoids for the treatment of diseases standing with free radicals and/or for the treatment of hormonal imbalance such as amenorrhea, menopause, hot flushes etc., is not proved by any data either. It is moreover entirely unclear which of the components actually present in the extract described therein (rhaponticin, deoxyrhaponticin, astrangin, piceatannol, anthracenosides, and the unanalyzed constituents present in a content of 10%) contribute to the asserted pharmacological activity or, where appropriate, are in fact absolutely necessary for the asserted synergism. The actual disclosure of FR 2 835 185 should therefore be restricted to the preparation of a specific, complex rhubarb extract by hydroalcoholic extraction of rhizomes of Rheum rhaponticum and the preparation of specific hydroxystilbene derivatives, and the production of various pharmaceutical formulations. In addition, there are doubts whether the complex extract disclosed in FR 2 835 185 can in fact be processed satisfactorily to tablets complying with the quality standards of the pharmaceutical industry.
There is thus a need for improved dosage forms for the extract ERr 731 and other compositions with similar active ingredients for more efficient treatment of various menopausal disorders which no longer have one or more of the disadvantages described above.